WO1989008113A1 - 3,4-DIHYDROTHIENO[2,3-d]PYRIMIDINE COMPOUNDS AND PHARMACEUTICAL APPLICATION THEREOF - Google Patents

Abstract

3,4-Dihydrothieno[2,3-d]pyrimidine compounds having immunomodulatory and oncostatic actions and represented by general formula (I) (wherein A represents C1-4? alkylene, R?1 represents H, alkyl, (optionally substituted) aryl or -N(R?7)(R?8), R?2, R?3 and R?4 each represents H, halogen, OH, optionally halogen-substituted alkyl, alkoxy, NO2?, CN or -N(R?9)(R?10), R?5 represents H, halogen, NO2?, NH2?, CN, alkyl or alkoxycarbonyl, R?6 represents H, halogen, NO2?, NH2?, CN, alkyl, alkoxycarbonyl, sulfonyl halide or -SO2?N(R?12)(R?13), or R?5 and R?6 may be taken together to form C3-6? alkylene chain) and pharmaceutical applications thereof are disclosed.

Description

 Specification

 3,4-Dihydrothieno [2,3—d] pyrimidine compound and its pharmaceutical use

 "Technical field"

 The present invention relates to a novel 2,3 dihydrodreno [2,3-d] pyrimidine compound useful as an immunomodulator or an anticancer agent, a salt thereof and a pharmaceutical use thereof.

 "Background technology"

 Several similar compounds have already been reported for thieno [2,3-d] pyrimidine compounds. For example, Chemical Abstract, 79, 6141 In has 3,4—dihydro-3- (2-cyclophenyl) -1,2,6—dimethyl-1-4-oxothieno [2,3-d Pyrimidine is synthesized as a metabolic analogue with a hypnotic effect, but its action is weak. Japanese Examined Patent Publication No. 47-422271 discloses that hexahydro 3—lower alkyl-1- [1] benzothieno [2,3-d1 pyrimidine—having central nervous system depressant and anti-inflammatory effects. The compounds disclosed in JP-A-52-68197 are 3,4-Dihydro-6- (N, N-dimethylsulfamoyl 4- 4-oxothieno [2,3-d. Bilimidine has been reported as a synthetic intermediate for compounds having antibacterial, antiviral, antibacterial, and plant growth regulating activities.

In addition, in the specification of Indian Patent No. 151966, certain chenovirimidine compounds used for the treatment of hyperlipidemia are described, and Drugs of the Fu Lure Vol. Pp. 1885-2 —Chlometinolay 5; 6, 7, 8 —Tetrahydride included in the patent It is described that oral benzo [b] cheno [2,3-d] pyrimidine-14 (3H) -one is useful as a hypolipidemic agent.

 Furthermore, Arch. Pharm. Vol. 309, pp. 908-913 (1976) states that 2—aminomethyl-1-3— (2—methylphenyl) -1,5,6,7,8 — It has been reported that tetrahydro (1) benzothieno [2,3-d3pyrimidine-14 (3H) -one compound was synthesized as the above-mentioned methapane analog.

 In recent years, drugs having an immunomodulatory effect have been widely used for the prevention or treatment of autoimmune diseases, the treatment of cancer, the reduction of side effects caused by anticancer drugs, the treatment of infectious diseases, and the like. Among them, injection or oral gold preparations have been recognized as useful as drugs against chronic rheumatoid arthritis, a type of autoimmune disease, but have many side effects. ing. Therefore, there is a need for a compound that has an excellent immunomodulatory effect and has few side effects.

 "Disclosure of the invention"

 Under the circumstances described above, the present inventors have conducted an intentional measurement for the purpose of providing an excellent immunomodulator, and as a result, have found that a novel 2,3-dihydrothieno [2,3-d) pyrimidine compound or its The present inventors have found that salt has a remarkable immunoregulatory effect as well as a control effect, and thus completed the invention.

The present invention has the general formula

{Wherein A represents a straight or branched alkylene having 1 to 4 carbon atoms. R ¹ represents hydrogen; alkyl; aryl (the aryl may be substituted); or a group represented by 1 N (R ⁷ ) (R ⁸ ). Provided that R ⁷ and R ⁸ are the same or different and represent hydrogen; alkyl; aralkyl (the aralkyl may be substituted); aryl (the aryl may be substituted); Or R ⁷ and R ⁸ may form a ring with the adjacent nitrogen atom, and the ring may further optionally include nitrogen, oxygen, sulfur, and> N—R ⁹ . [However, R ⁹ is hydrogen; alkyl optionally substituted by hydroxy or alkyl-substituted amino; cycloalkyl; formyl; aralkyl (the aralkyl may be substituted); (The aryl may be substituted); arylalkenyl; heterocycle; arylcarbonyl (the arylcarbonyl may be substituted); or heterocyclic carbonyl.

R ² , R ³ and R ⁴ are the same or different and each is hydrogen halogen; hydroxy; alkyl optionally substituted by halogen; alkoxy; nitro; cyano; or one N (R ¹ ) (R ¹ Represents a group represented by ¹ ). However, R ¹⁰ and RH are the same or different and each represents hydrogen; alkyl; alkanol; or arylcanolebonyl (the arylcarbonyl may be substituted). I forgot.

R ⁵ represents hydrogen; hydrogen, rhogen, nitro, amino, cyano, alkyl, or alkoxycarbonyl.

R ⁶ is hydrogen; nodogen; nitro; amino; cyano; alkyl; anoreoxyl-norrebonyl;

- represents a group represented by ^{_{S 0 2 N (R IZ)}} (R 13). Provided that R ¹² and R ¹³ are the same or different and are hydrogen; alkyl; cycloalkyl; aralkyl (the aralkyl may be substituted); aryl (the aralkyl may be substituted); Li Ruarukeniru; alkyl or § Li Lumpur (the § Li Lumpur may be substituted) or represents Karubonirua Mi Roh Al killed substituted by; and the nitrogen atom to which or R ¹² and the R ¹³ is adjacent DOO also form a monitor ring rather good, the ring further nitrogen, oxygen,> N-R ¹⁴ a may optionally be interposed. Provided that R ¹⁴ is hydrogen; alkyl which may be substituted by a hydroxy or alkyl-substituted amino; cycloalkyl; formyl; aralkyl (the aralkyl may be substituted); Aryl is optionally substituted); aryl alkenyl; heteroaryl; aryl carbonyl (the aryl carbonyl may be substituted); or heterocyclic carbonyl.

R ⁵ and R ⁶ may combine together to form an alkylene group having 3 to 6 carbon atoms. However, when R ⁶ represents hydrogen; no, rhogen; nitro; amino; cyano; alkyl; or alkoxycarbonyl, or R ⁵ and R ⁶ are bonded together to have 3 to 6 carbon atoms. R ¹ represents one N (R ⁷ ) (R ⁸ ) (However, R ⁷ and R ⁸ are as defined above). When R ⁵ and R ⁶ are combined to form an alkylene chain having 3 to 6 carbon atoms, R ^z , R ³ and R represent groups other than alkyl. }

 3,4—dihydrothieno [2> 3-d1 pyrimidine compound or a salt thereof represented by the general formula:

(In the formula, A represents a straight-chain or branched alkylene having 1 to 4 carbon atoms, and R ′ represents hydrogen; alkyl; aryl (the aryl may be substituted.) Or a group represented by N (R ⁷ ) (R ⁸ ), provided that R ⁷ and R ⁸ are the same or different and are hydrogen; alkyl; aralkyl (the aralkyl may be substituted) Aryl (which may be substituted) represents cycloalkyl; or R ⁷ and R ⁸ may form a ring with adjacent nitrogen atoms, the ring further comprising: Nitrogen, oxygen, sulfur,> N—R ⁹ may be optionally intervened, wherein R ′ is hydrogen; alkyl optionally substituted by hydroxy or alkyl-substituted amino; cycloalkyl; Mil; Aralkyl Which may also be); § Li Lumpur (those 該A reel may be substituted); § reel alkenyl; A heterocyclic ring; arylcarbonyl (the arylcarbonyl may be substituted); or heterocyclic carbonyl. ]

R ^2, R ^3, and! ? ⁴ are the same or different and each is hydrogen; represent or a N (R ^IO) (groups I Table by R ^1; halogen; human Dorokishi; halogenated alkyl optionally substituted with; alkoxy; two collected by filtration; Shiano However, R ^IE and R ¹¹ are the same or different and each represents hydrogen; alkyl; alkanol; or arylcarbonyl (the arylcarbonyl may be substituted).

R ⁵ represents chromium; chloro, rhogen; nitro; amino; cyano; alkyl; or alkoxycarbonyl.

R ⁶ is hydrogen; nodogen; nitro; amino; cyano; alkyl; alkoxycarbonyl; nodogenated sulfonyl;

-Represents a group represented by S 0 ₂ N (R ^{1 Z} ) (R ^{, 3} ). However, hydrogen R ^{1 2} and R ^{1 3} are the same or different; alkyl; Shi click Roarukiru; Ararukiru (the Ararukiru may be substituted); § Li Lumpur (the § Li Lumpur substituted may be); § reel alkenyl; or alkyl or § Li Lumpur (the § Li Lumpur represents Karubonirua Mi Roh Al killed substituted with may) be substituted; or R ^{1 2} and R ^{1 3} May form a ring with an adjacent nitrogen atom, and the ring may optionally further include nitrogen, oxygen, and> N—R ″, where R ″ is hydrogen; Alkyl which may be substituted with a droxy or alkyl-substituted amino; cycloanolekyl; formyl; aranorekyl (this aralkyl may be replaced); aryl (the aryl is substituted) An arylalkenyl; a heterocyclic ring; an arylcarbonyl (the arylcarbonyl may be substituted); or a heterocyclic carbonyl.

R ³ and R ⁶ may bond together to form an alkylene chain having 3 to 6 carbon atoms. }

 And a salt thereof as an active ingredient.

 The above definitions will be described in more detail for each substituent.

 With respect to A, a straight-chain or branched-chain alkylene having 1 to 4 carbon atoms is exemplified by methylene, ethylene, trimethylene, tetramethylene, propylene, and isopropylidene. It can be.

With respect to R ¹ , alkyl is straight-chain or branched, preferably alkyl having 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl). Say.

Regarding R ¹ , aryl (the aryl may be substituted) is preferably alkyl (alkyl having 1 to 4 carbon atoms such as methyl, ethyl, etc.), norogen ( Refers to phenyl which may be substituted with chlorine, bromine, fluorine and the like, and alkoxy (alkoxy having 1 to 4 carbon atoms such as methoxy and ethoxy).

For R ⁷ and R ⁸ in -N (R ⁷ ) (R ⁸ ), alkyl is straight or branched chain, preferably alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, Propyl, isopropyl, butyl and tertiary butyl.

"With respect to R ⁷ and R ^8, a cycloalkyl, the preferred and rather is a number three to seven of a cycloalkyl carbon, for example consequent opening pentyl, Cyclohexyl, cycloheptinolate power.

R ⁷ and R ⁸ may be substituted with alkoxy (for example, alkoxy having 1 to 4 carbon atoms such as methoxy and ethoxy), halogen (fluorine, chlorine and the like), and the like. Alternatively, it is an aryl with 6 to 10 carbon atoms. Such aryls include, for example, phenyl, P-methoxyphenyl, and 0-cloth phenyl.

Regarding R ⁷ and R ⁸ , the aralkyl may be substituted by alkyl (alkyl having 1 to 4 carbon atoms such as methyl and ethyl) and the like, preferably with aralkyl having 6 to 10 carbon atoms. And preferably has 1 to 4 carbon atoms, such as benzyl, p-methylbenzyl, and 2-phenylethyl.

When R ⁷ and R ⁸ form a ring together with an adjacent nitrogen atom, the ring is preferably a 4- to 8-membered ring, and may be either saturated or unsaturated. Examples of such a ring include 1-virolyl, 1-pyrrolidinyl, piperidino, homobiperidino and the like. The ring may optionally further intervene nitrogen, oxygen, sulfur,> N—R ⁹ , such as, for example, 1-biperazinyl, 1-homobidurajur, 1-imidazolyl , 1-triazolyl, morpholino, thiomorpholino, and thiazolidinyl.

And閡to R ^9, alkyl is rather good either was Shizuma straight of branched chain, is if rather preferably having 1 to 6 carbon alkyl, for example methylation, Echizore, Puropizore, Lee an isopropyl, butyl, I Sobutyl, pliers and hexylka. The Tokinai alkynole may be substituted with hydroxy, such as, for example, hydroxy. Xymethicil, 2-hydroxy sheptyl, and 2-hydroxypropyl. Examples of the group in which the alkyl is mono- or di-substituted with alkylamino include mono- or dialkylaminoalkyl, and the alkyl substituted with the amino generally has 1 to 4 carbon atoms. Such substituted alkyls include, for example, 2-methylaminopropyl, 2-ethylaminopropyl, and 3-dimethylaminopropyl.

Regard R ^9, Sik port alkyl, the preferred and rather a number 3-6 a cycloalkyl carbon, for example consequent Ropuro pills, sik b pentyl, the key sill to consequent ii like.

Regard R ^9, § Li Lumpur alkyl (methylation, carbon number 1 to 4 alkyl, such as Echiru), alkoxy (main butoxy, and 1 carbon atoms, such as e butoxy 4 alkoxy), halogen (full Tsu And is preferably an aryl having 6 to 10 carbon atoms, which may be substituted with, for example, 0 to methoxyphenyl. , 2, 4 — dimethoxyphenyl, P — trinole, P-chlorophenyl, 3, 4 — difluorophenyl.

Regard R ^9, Ararukiru has a preferred to rather few 1-3 § alkyl carbon, is preferred to rather a 6 to 1 0 amino § Li Lumpur carbon, Nono androgenic (full Tsu-containing, chlorine, etc. ), Alkylated nitrogen (such as trifluoromethyl) and the like. Such groups include, for example, benzyl, p-chlorobenzene, m-triphenylolenomethylbenzine, 0-funoreobenzobenzene, 2-phenylenole, 3-phenylpropyl. .

For R ⁹ , aryl alkenyl may be straight-chain or branched It preferably has alkenyl having 2 to 4 carbon atoms and preferably has 6 to 10 carbon atoms, such as cinnamyl.

Regard R ^9, § Li Rukarubo sulfonyl Non de port alkoxy, Nono androgenic (full Tsu-containing, chlorine, etc.) rather it may also be substituted with the like, preferably one having a Ariru 1 0 6 carbon atoms There are, for example, Penzyl, p-black benzoyl, and 0-hydroxybenzoyl.

Regard R ^9, heterocycle nitrogen in the heterocyclic carbonyl, oxygen, a 1 or 2偭有saturated or unsaturated heterocyclic ring heteroatoms such as sulfur, be two or more rings fused ring For example, 2—Froile, 2—Tenoyl, and Nicotine.

With respect to R ² , R ³ and R ⁴ , halogen refers to fluorine, chlorine, bromine and iodine. Alkyl in which halogen may be substituted is straight-chain or branched-chain alkyl having preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc. Trifluoromethyl. Alkoxy is preferably alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy and propoxy.

— With respect to R ¹ °, R ¹¹ in N (R ¹ ) (R ¹¹ ), alkyl is a straight or branched chain, preferably alkyl of 1 to 4 carbon atoms, eg Examples include methyl, ethyl, propyl, isopropyl, butyl, and tertiary butyl.

With respect to R ¹ R ¹¹ , the alkanol may be straight-chain or branched, Preferably, it is an alkanol having 2 to 5 carbon atoms, such as acetyl, propionyl, butyryl, and p-vinyl.

In relation to R ¹ ° and R ¹ ′, arylcarbonyl may be substituted by halogen (fluorine, chlorine, etc.), and preferably has 6 to 10 carbon atoms. For example, benzoyl, p-black benzoyole.

Regard R ^5, alkyl is straight or branched, is preferred to rather alkyl of 1 to 4 carbon atoms, for example methylation, Echiru, propyl, I Sopu port pills, heptyl, tert-butyl Is raised.

Regard R ^5, alkoxycarbonyl, preferred and rather has a number 1-4 alkoxy carbon of the Shizuma straight branched, for example main Tokishikanoreboni? And ethoxycanolebonole, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and tertiary butoxycarbonyl.

Regard R ^6, alkyl straight Shizuma had a branched, is preferred to rather alkyl of 1 to 4 carbon atoms, for example methylation, Echiru, propyl, I Sopuro pills, heptyl, tertiary butyl can give.

Regard R ^6, alkoxycarbonyl, preferred and rather is Chokukusarima others have 1 to 4 carbon atoms branched alkoxy key sheet, for example, main butoxycarbonyl, et butoxycarbonyl, propoxycarbonyl Kano levo two Le, Isopropoxycarbonyl, butoxycarbonyl, and tertiary butoxycarbonyl. .

Regard R ^6, and halogen in Nono halogenated sulfonyl called off Tsu-containing, chlorine, bromine, iodine, in the said group, click port B sulfonyl and the like, for example. -With respect to R ¹² and R ¹³ in S 0 _z N (R ¹² ) (R ¹³ ), alkyl is straight-chain or branched, preferably alkyl having 1 to 4 carbon atoms, for example, methyl, Ethyl, propyl, isop pill, butyl and tertiary butyl.

Regarding R ¹² and R ¹³ , cycloalkyl is preferably cycloalkyl having 3 to 7 carbon atoms, and examples thereof include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Regarding R ^{1 Z} and R ¹³ , aryl is alkyl (alkyl having 1 to 4 carbon atoms such as methyl and ethyl), alkoxy (alkoxy having 1 to 4 carbon atoms such as methoxy and ethoxy), It may be substituted with a halogenated alkyl (such as trifluoromethyl) or the like, and is preferably an aryl having 6 to 10 carbon atoms, for example, phenyl, P-methoxyphenyl, p-triphenyl. Nore, HI — Trifluoro-methyl phenyl.

Regarding R ^{1 Z} and R ¹³ , aralkyl preferably has 1 to 3 carbon atoms and preferably 6 to 10 carbon atoms, and may be substituted with halogen (fluorine, chlorine, etc.). Good. Examples of such a group include benzyl and P-fluorobenzyl.

And orchids R ^12, R ^13, § reel alkenyl's was Shizuma straight branched, and alkenyl number 2-4 carbons if verses like, preferably having from 6 to 1 0 amino Ariru carbon atoms , For example, Cinna Mill.

With respect to R ^{1 Z} and R ¹³ , the alkyl-substituted carbonyl amino alkyl has an alkyl-substituting ability which is favorable for straight-chain or partial-separation. Or an alkanol having 2 to 5 carbon atoms, and the alkyl is a straight-chain or branched alkyl, preferably having 1 to 6 carbon atoms, for example, 2-acetylaminoethyl. , 4-acetylaminobutyl and 6-propionylaminohexyl. In addition, aryls of aryl-substituted carbonylamino alkynoles may be substituted with halogens (fluorine, chlorine, etc.), preferably aryls having 6 to 10 carbon atoms. And alkyl is a straight-chain or branched-chain alkyl, preferably having 1 to 6 carbon atoms, as described above. Such groups include, for example, 4-benzoylaminobutyl, 6

-(p-black benzoyl) amino-hexyl.

If the R ^{1 2} and R ^{1 3} form a ring together with the nitrogen atom to隳接, preferably rather it is a 4-membered to 8-membered ring, saturated, any der connexion may be unsaturated. Examples of such a ring include 11-pyrrolyl, 11-piperidinyl, piperidino, homopiperidino and the like. The ring may further optionally include nitrogen, oxygen, sulfur, and> N—R ¹⁴ , and examples of such a ring include, for example, 1—piperazul, 1 homopiperazinyl, 1 Imidazolyl, 1-triazolinole, morpholino, thiomorpholino, and thiazolidinyl.

With regard to R ¹³ , the alkyl-substituted amino may be substituted alkyl; cycloalkyl; aryl (the aryl may be substituted); aralkyl (the aralkyl may be substituted). An arylalkenyl; a heterocyclic ring; a formyl group; an arylcarbonyl (the arylcarbonyl may be substituted); and a heterocyclic carbonyl, each of which is R ⁸ . Examples similar to those described above are exemplified.

The group in which R ⁵ and R ⁶ are bonded together to form an alkylene chain having 3 to 6 carbon atoms is defined as an adjacent thiophene ring and cyclopentathiophene ring, tetrahydrobenzothiophene, and cycloheptat. Forming an orphan ring.

 Salts of the compound of the present invention represented by the formula (I) include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and oxalic acid, fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, salicylic acid and the like. Pharmaceutically acceptable acid addition salts with organic acids are preferred. There are also hydrates (monohydrate, tetrahydrate, hydrate, etc.).

 When a chiral carbon atom is present in the compound (I) of the present invention, the present invention also covers each optical isomer.

—Compound Φ of general formula (I), a preferred group of compounds has R ⁶

^{_{- S 0 2 Ν (R,}} 2) (R 13) ( provided that, R ^12, R ¹³ is as defined above.) Compound represent, or, R ⁶ is hydrogen; halogen; two collected by filtration; § amino; Cyan; alkyl; or alkoxycarbonyl, or a group in which R ^s and R ⁶ are bonded together to form an alkylene chain having 3 to 6 carbon atoms, and R ¹ is —N (R) ( R ⁸ ) (wherein, R ⁷ and R ⁸ are as defined above). Further, a more preferred compound is 3,4-dihydro-3- (2-chlorophenyl) 1-2- (4-ethyl-1-piperazinyl) methyl-4-1-oxo-6-sulfamoyl thieno [2> 3 — D] pyrimidine; 3, 4 — dihidroxy 3 — (2-cyclophenyl) 1 2 — (4-ethyl 1 — piperazinyl) methyl 5, 6 — dimethyl 4-oxothieno [2, 3— d] pyrimidine; 3> 4, 5, 6, 7, 8-hexahi draw 3-(2-black feninole) 1 2-(4-ethyl 1-piperazinyl) methyl 1 4- Oxo (1) benzothieno [2,3-d) pyrimidine; 3,4-dihydro-3-(2-chloro-phenyl)-6-ethoxycarbonyl-2-(4-ethyl-1-bipera Di-n-yl) methyl 1 5-methinole 4-oxothieno [2,3-d) pyrimidine; 3, 4-dihydro 3-(2-cyclophenyl)-2-methyl 4-oxo 1 6—Sulfa Moi Lucieno [2,

3-d) pyrimidine; 3,4-dihidro 3-(2-chlorophenyl) 1-6-ethyl-1-2-(4-ethyl-1-piperazinyl) methyl-4-oxothieno [2, 3-d] pyri 3; 4 zihi draw 3— (2-fluorophenyl) 1-2— (4—methyl-1—pyrazur) methyl 1-4—oxo1-6—snorrefa moluthieno [2,3— d] pyrimidine; 3,4—dihydro-3- (2-chlorophenyl) -1-2—morpholinomethyl-4—oxo-6—sulfamoyl thieno [2,3—d] pyrimidine 3,

4—Dihydro 6—Bromo 3— (2—Mouth phenyl) 1—2 (4—Chetinole 1—Pipera Gininole) Metinole 4—Oxocheno [2,3—d] pyrimidine; 3, 4— 1-6 — Black Mouth — 3 — (2 — Black Mouth Hue Nil) 1 2 — (4 — Ethyl 1 1 — Pio Lajur) Methyl 1 4-Oxothieno [2,3-d1 , 3, 4 Jihi Draw 3 — (2 — Chloro 4 12 Trofenyl) 1 2 — (4 1 Etyl 1 1 — Pipera Ginore) Methyl 1 6 — 2 Tro 1 4 — Oxothieno [2,3—d] pyrimidine; and 3,4—dihydro-1-3— (2—black mouth feninole) 1-2— (4—methyl Lou 1 —Pydra Jur) Methyl 1 —Oxo 1 6 —Sulfamoyl thieno [2,3-dj Pyrimidine and its compounds selected from salts and hydrates.

 The compound represented by the formula (I) of the present invention can be produced, for example, by the following method.

First law

 Equation (H)

^{(Wherein, A, R 1, R 2} , R 3, R 4 and R ⁵ are the consent our ^c: Ru fit.)

By reacting a compound represented by the formula with σ-genosulfonic acid (especially, chiro-sulfuric acid), a halogenated sulfuryl (especially, sulfuryl chloride), or after sulfonation. By the formula (I)

(式中、 X ¹ はハロゲンを表わし、 A、 R ¹ 、 R ² 、 R ³ 、 R および R ⁵ は前記と同意義である。 ） (I)

(Wherein X ¹ represents halogen, and A, R ¹ , R ² , R ³ , R and R ⁵ are as defined above.)

 The compound represented by is produced.

 This reaction is performed, for example, as follows. That is, ① formula

The compound of (II) is treated with chlorosulfonate in the absence of a solvent or in an organic solvent such as chloroform and carbon tetrachloride at a temperature from room temperature to 100 ° C.

(Preferably from 70 to 100'C) or (2) the compound represented by the formula (H) is reacted with an organic solvent such as tetrahydrofuran or hexane in sulfuric chloride. ③ The compound of formula (（) is heated to 70 to 100 with fuming sulfuric acid or 95% sulfuric acid-acetic anhydride, and then treated with a base to give a sulfonate (Natrile). The salt can be manufactured by heating (100 to 20 O'C) with phosphorus pentachloride and phosphorus oxychloride.

 The compound of the formula (Π) can be prepared by the method described in Chemical'Abstract, 79, 61411π and M * S. Msnkss et al. (J. Med. Chem. 15, 106 (1972)). Can be manufactured.

Second law

 The compound of the formula (ΠΙ) can be further produced as follows.

 (1) Nitrogenation of the compound of formula (Π) gives the compound of formula (IV)

(式中、 A、 R¹ 、 R² 、 R³ 、 R ⁴ および R⁵ は前記と同意 我 める。 ) (IV)

(Wherein, A, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)

The compound represented by is produced.

 The nitration reaction is carried out by a method known per se, for example, a method of heating with nitric acid to 50 to 60 ° C. in the presence of sulfuric acid, a method of reacting with nitric anhydride at a low temperature, and a method of fuming nitric acid-monoglacial acetic acid. And (2) reducing the compound of formula (IV) to reduce the compound of formula (V)

^H

(Wherein, A, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)

To produce the compound represented by

 The reduction includes chemical reduction, for example, reduction under acidic conditions (eg, with zinc, iron, tin chloride, etc. and acetic acid, concentrated hydrochloric acid, etc.), reduction with sulfides (sodium sulfide, sodium polysulfide, etc.). Heating reflux in sodium hydroxide, sodium hydrogen sulfide, sodium thiosulfate, ammonium sulfide, etc.), Raney nickel, 10% palladium oxide, palladium oxide, etc. A method of adding hydrogen is exemplified.

③ The compound of formula (V) is diazotized and then treated with cupric sulfur monoxide to produce the compound of formula (m). That is, sodium nitrite, a strong acid (sulfuric acid, concentrated hydrochloric acid, hydrogen bromide, etc.) and a weak acid (acetic acid, etc.) are reacted with the compound of the formula (V) at 0 to 5 to obtain a diazo compound. A salt of a compound of formula (M), for example, 6-monochloride, is prepared by preparing a salt of the compound and adding it to a solution of cupric halide (cupric chloride, cupric bromide, etc.) and sulfur dioxide in acetic acid. A sulfonyl-substituted compound, a 6-sulfonyl bromide-substituted compound and the like are produced.

 Third law

 Compounds of formula (IE) and formula (VI)

R ¹²

 H N ヽ (VI)

R ¹

(Wherein, R ¹² and R ¹³ are as defined above.)

By reacting with a compound represented by the formula (VI)

(Wherein, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹² and R ¹³ are as defined above.)

Can be produced.

The reaction is preferably carried out in water or black form, methylene chloride-tetrahydrofuran, dioxane, acetonitrile, ether- The reaction is carried out in an organic solvent such as ethyl acetate, benzene, toluene, dimethylformamide, and dimethylsulfoxide, or in a mixed solvent Φ thereof. In addition, the bold reaction is carried out by using an appropriate organic base (triethylamine, pyridine, dimethylaminopyridine, diisopropyl pyrethylamin, etc.) or an inorganic base (lithium carbonate, sodium carbonate). And sodium bicarbonate). The reaction temperature is preferably a temperature from 120 ° C. to the boiling point of the solvent.

4th law

Ceremony (Cor)

(Formulas Φ and X ² are halogen, and A, R ² , R, R ⁴ , R ⁵ R ¹² and R ¹³ are as defined above.)

And a compound represented by the formula (Κ)

(Wherein, R ⁷ and R ⁸ -are as defined above.)

By reacting with a compound represented by the formula (X)

(Wherein, A, R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹² and R ¹³ are as defined above.)

 Can be produced.

 The reaction is usually carried out in a suitable solvent (eg, water, acetate, black formaldehyde tetrafluorofuran, acetonitril, dimethylformamide, or a mixture thereof). , Organic bases (triethylamine, pyridin, dimethylaminopyridin, disopropylethylamine, etc.) or inorganic bases (such as potassium carbonate and sodium carbonate. The reaction is carried out at a temperature of 0 to 80 in the presence of sodium hydrogen.

The compound of the formula (1) is obtained by converting a compound of the formula (W) (wherein R ¹ represents hydrogen or alkyl) from N-α-mosacyl imidide, Ν-chlorosac- cinimide, bromine, chlorine, It is produced by reacting with a halogenating agent such as fluorine.

This halogenation reaction is usually carried out in an organic solvent such as acetic acid, carbon tetrachloride, black form, benzene, toluene, dimethylformamide, etc., in the presence of peroxide (dibenzoyl peroxyside, m-black). It occurs in the presence of perbenzoic acid, t-butyl hydroperoxide, peracetic acid, etc.) or azoisobutyronitrile (AIBN) or under light irradiation. Fifth law

 ① By reacting the compound of formula ()) with a halogenating agent such as N-bromosuccinimide, N-cyclosuccinimide, bromine, chlorine or fluorine, the formula (XI)

(Where Ha £ represents chlorine, bromine, and fluorine; A, R ¹ , R ²

R ³ , R ⁴ and R ⁵ are as defined above. )

To produce the compound represented by

 The halogenation reaction proceeds under the conditions described in the fourth method.

(2) The compound of formula (XI) is treated with cuprous cyanide in an organic solvent such as dimethylformamide or pyridine at 150 to 250 after treatment with the compound of formula (XI).

(Wherein, A, RR ² , R ³ , R ⁴ and R ⁵ are as defined above) are produced. 6th law

 Expression (xm)

 o

R

(In the formula, R ′ _a represents hydrogen, halogen, alkyl or aryl, and R ² , R ³ , R ⁴ , R ³ and R ⁶ have the same meanings as described above.)

The compound of the formula (I) is produced by closing the compound represented by the formula (I) or, when R is a halogen, by reacting with the compound of the formula (K) and then closing the ring.

 In this ring closure reaction, the compound of the formula (XII) is dissolved in a solvent such as anhydrous benzene, anhydrous toluene, anhydrous xylene, or the like, in an aqueous solution of oxychlorine, oxybromide, trichloride, It is carried out by heating and refluxing in the presence of thione, thionyl chloride and the like.

 When R'a is halogen, the reaction of the compound of the formula (K) is carried out in the same manner as in Method 4.

 The compound of formula (ΧΠ) has the formula (IV)

(Wherein, R ^z , RRR ⁵ and R ⁶ are as defined above.) And a compound represented by the formula (XV)

R ' _a — ACOOH (V)

 (Wherein, R is as defined above.)

Is produced by reacting-with a compound represented by the formula or a reactive derivative thereof.

 Examples of the reactive derivative of the compound of the formula (XV) include an acid halide, an acid anhydride, an active amine, an active ester, and a nitrile. As the derivatives, specifically, for example, acid halides (acetyl chloride, chloroacetyl chloride, etc.), and acetonitrils (chloroacetonitrile, promorecetonitrile) Etc.), acetamides (chloroacetamide) and the like.

 This reaction is carried out in an appropriate solvent (chloroform, methylene chloride, toluene, benzene, etc.) in the presence of a base (triethylamine, pyridine, diisopropylethylamine, etc.). This is done by reacting at ~ 50'C.

7th law

Formula (XVI)

 β no S N CW

(XVI) o

(Wherein, R ⁵ and R ⁶ are as defined above.)

(Wherein R ² , R ³ and R ⁴ have the same meanings as described above). In the coexistence of a substituted aniline represented by the formula ( ¹ ), when the ring is closed, or when R ¹ is halogen, a compound of the formula (K) is used. The reaction yields the compound of formula (I).

 This reaction is carried out by heating to reflux with phosphorus oxychloride, phosphorus trichloride, thionyl chloride, etc., and the reaction temperature is the same as in Method 4 when the compound of formula (K) when R represents halogen. It is. Preferably it is 30 to 70C.

 The compound of formula (I) is converted into a pharmaceutically acceptable salt by a method known per se, and the salt is converted into a free compound by a method known per se. In addition, when a chiral carbon atom is present in the compound of the formula (I), it is generally obtained as a racemate, but this can be separated into optical isomers by a conventional method to obtain an optically active compound. It can be synthesized, or can also be synthesized by using an optically active starting compound.

The compound of formula (I), which is the object compound of the present invention, and a pharmaceutically acceptable salt thereof have an inhibitory effect on the production of antibodies against mammals such as humans, mice, dogs, mice and rats. Has immunomodulatory and anti-cancer effects such as delayed hypersensitivity reaction, etc., and has chronic Minz 閔 rheumatism, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease , Systemic (organ non-specific) autoimmune disease, autoimmune disease such as periarteritis nodosa, and dying vasculitis; autoimmunity Storage for thyroid disease, autoimmune diabetes, myasthenia gravis, Cedaren syndrome, anti-GBM antibody disease (autoimmune nephritis), autoimmune heart disease, autoimmune blood disease, autoimmune liver disease, etc. Specificity It is useful as a prophylactic or therapeutic agent for autoimmune diseases, etc., or as a rejection inhibitor or anticancer agent during transplantation of various organs such as human skin and various mammalian skin, bone marrow, and the like.

 Pharmacological experiment example 1. Antibody production inhibitory action

 Using a male MRLZ £ mouse (6 mice per group), a test compound suspended in 0.5% methylcellulose was orally administered (10 nigZkg) for 4 weeks, 12 to 15 weeks of age, and 16 At the age of the week, serum was collected by fundus bleeding. The amount of IgG, IgM, anti-DNA antibody and IgM rheumatoid factor contained in this serum was measured by a standard ELISA method, and the inhibition rate (%) with respect to the control group was determined. Table 1 summarizes the results. In addition, for these experimental groups, the administration was further continued, the final death date was confirmed, and the average number of survival days was determined (Table shows the ratio when the control group was set at 100%). . In the control group, 0.5% methylcellulose was intraperitoneally administered for the same period.

 Table 1 Serum antibody levels (suppression rate,

Compound number Average survival

 IgG IgM anti-DM antibody rheumatoid factor Days Example 2 70.0 75.8 79.4 49.5 127 Example 1 1 50.4 90.9 76.8 32.6 115

As shown in Table 1, the compound of the present invention was The autoimmune disease model MRL £ was shown to have an inhibitory effect on the increase in antibody production with age of mice, and to show a tendency to prolong life.

 Pharmacological experiment 2. Effect on adjuvant arthritis

 (a) Preventive experiment ''

8-1 0-week-old male L Ewis rats of the (Seiwa Experimental Animals fed) and 1 group of 8 animals, killed Mycobacterium tuberculosis suspended in fluid paraffin as adjuvant preparative (R ₃₅ H ₅ type) 0.5 mg / 0.1 ^ was inoculated intradermally in the ridge. The test compound was orally administered once a day from the day of sensitization to the 21st day. The paw volume was measured by the water displacement method before and after the adjuvant vaccination and at 10, 15, 18, 21, and 28, and the effect was judged based on the paw volume before the adjuvant vaccination. The change value at each time point was determined, and the significance for the control group was determined by one-way analysis of variance. The inhibition rate was calculated from the change value on the 21st day. As a result, the compound of Example 2 and the compound of Example 11 showed an inhibitory rate of 34.6% and 55.3%, respectively, by oral administration of 30 mg Zk'g.

 () Treatment experiment

Animals sensitized in the same manner as in (a) and having developed arthritis on the 15th day were selected. The test compound was orally administered once a day from the 15th day to the 30th day. To determine the effect, the inhibition rate relative to the control group was calculated from the change value on day 30 based on the paw volume on day 15 as a reference. As a result, the compound of Example 2 exhibited a suppression rate of 95.0% at the dose of 10 mg / kg and a dose of 139.6% at the dose of 30 mg / kg, and the compound of Example 11 exhibited a suppression rate of 10 mg / k'g. The administration showed a 12.48% inhibition rate, and the 30 mg / kg administration showed a 132.7% inhibition-rate. Pharmacological experiment 3. Effect on rat collagen arthritis

 (a) Prevention experiment-Male Sprague weighing 150-200 g-Type II collagen emulsion 1 (0.1 N acetic acid 2 mg / ffl) in the shaved back skin of Dawley rats £ and Freund's incomplete adjuvant (1) were administered in 5 divided doses, and Ί days later, the emulsion 0.2 was administered intradermally to the ridge and resensitized. The test compound solution was orally administered once a day from the sensitization day to the 27th day. The paw volume was measured over time before the administration of collagen, the change value was determined based on the paw volume before the administration, and a one-way analysis of variance was performed to determine the significance with respect to the control group. The suppression rate was calculated from the change on the 19th day. As a result, the compound of Example 11 showed an inhibition rate of 24.1% when administered at 10 mgZkg, and 45.4% when administered at 30 mg / kg.

 (b) Treatment experiment

 Animals sensitized in the same manner as in (a) and having developed arthritis on the 14th day were selected, and 6 animals per group were selected. The test compound solution was orally administered once a day from 14 to 27 days. To determine the effect, the inhibition rate relative to the control group was determined from the change value on day 30 based on the paw volume on day 14 as a reference. The compound of Example 11 showed an inhibitory rate of 192.5% at a dose of 30 mgZkg.

Pharmacological experiment 4. Effect on mouse glomerulonephritis

) と F C Aとの 1 ： 1 のェマルジヨ ンを作成し、 このェマルジヨ ン 3 を脱毛したゥサギ背部皮内に数力所に分割して投与した。 これ を 1週毎に計 5回感作し、 最終感作から 1 0 日目にゥサギ頸動 脈より全採血し抗 G B M血清を得た。 次に、 ^サギ免疫グロブ リ ン （ R G G、 シグマ社） を生理食塩水溶液に溶解した液 （ 4 rag/ ) と F C Aとの 1 ： 1 のェマルジヨ ンを体重 2 0 g前後 の雌性 C 5 7 B £ /" 6 マウス （ 1 群 9〜 1 0匹） 腹腔内に 0.25 投与して、 マウス糸球体腎炎を作成した。 5 日後、 尾静脈よ り抗 G B M血清を 0. 0 5 静脈内投与し、 経日的に尿タ ンパク 量を測定した。 尿タ ンパク量は陰性 0点、 痕跡 1点、 3 0 mg/ ^ 2点、 1 0 0 mg/ 3点、 3 0 0 mg c¾ 4点および 2 0 0 0 ノ^以上 5点でスコ アを求め、 各群の平均スコアを算出した。 試験化合物液は抗 G B M血清投与より 1 5 日間連統経口投与し た。 作用は、 抗 G B M血清投与日の尿タ ンパク量のスコアを基 準に 1 6 日目の変化値から対照群に対する抑制率により評価し た。 その結果、 実施例 1 1 の化合物は 1 0 ragZkg投与で 3 5. 2 % 3 0 mgZk 投与で 9 2. 9 %の抑制率を示した。 GBM Glomerular basement membrane obtained from mouse renal cortex) Suspend the Takasha fraction to 2% to 0% in physiological saline, and use Freund's complete adjuvant (FCA and tongue-) and 1: 1 Create an emulsion and remove the emulsion It was divided into several dorsal sites and applied to the back of the giant. This was sensitized every week for a total of 5 times, and on day 10 after the final sensitization, whole blood was collected from the egret carotid artery to obtain anti-GBM serum. Next, a solution of persimmon immunoglobulin (RGG, Sigma) dissolved in a physiological saline solution (

) And FCA were prepared in a 1: 1 emulsion, and this emulsion 3 was intracutaneously applied to the back of the depilated perch at several places. This was sensitized a total of 5 times every week, and on the 10th day after the final sensitization, whole blood was collected from the egret carotid artery to obtain anti-GBM serum. Next, a 1: 1 emulsion of a solution of 4 heron immunoglobulin (RGG, Sigma) dissolved in a physiological saline solution (4 rag /) and FCA was added to a female C57B of approximately 20 g in weight. £ / "6 mice (9 to 10 mice per group) A mouse glomerulonephritis was created by intraperitoneal administration of 0.25. After 5 days, 0.05 g of anti-GBM serum was intravenously administered via the tail vein. Urinary protein levels were measured daily.Negative 0 points, 1 trace, 30 mg / ^ 2 points, 100 mg / 3 points, 300 mg c¾ 4 points and 2 points The score was calculated from 5 points above and below 0, and the average score was calculated for each group.The test compound solution was orally administered for 15 days from the administration of the anti-GBM serum. Was evaluated based on the urinary protein level score based on the change in the control group from the change on day 16. As a result, the compound of Example 11 was treated with 10 ragZkg at 35.2% 3 0 mgZk Showed a suppression rate of 92.9%.

Pharmacological experiment example 5. Effects on experimental allergic uniencephalomyelitis

A 40% emollient was prepared from a 0.5% ethanol solution of the cerebral cerebrospinal cord, and an equal amount of Freund's complete adjuvant was added to form an emulsion, 10 animals per group. The Male W Istar La "Roh door was 0.1 ^ by injection in both hind legs躕of (body weight 2 7 0~ 3 3 0 g) . At the same time, 0.5 to 2 X 1 0 ⁹ pieces of whooping cough killed on both thigh muscle囱内1 The mice were sensitized by injection in increments of 5. The method of determining the onset of experimental allergic monoencephalomyelitis was determined by Le Vine et al. (Arch. Int. Pharmacodyn. Ther. 230: 309, 1977). The test compound solution was orally administered continuously for 20 days from the day of sensitization, and 30 mg of the compound of Example 11 was obtained. The mean onset day was 20.5 ± 2.30 days when administered / kg, whereas that of the control group was 12.0 ± 0.35 days. Significantly delayed the onset of experimental allergic encephalomyelitis and reduced the incidence by 50%.

Pharmacological experiment 6. Delayed hypersensitivity

 Delayed type hypersensitivity was induced according to the method of Uyeki et al. (Proc. Soc. ExpU. Biol. Med. 132: 1140-1146, 1969). Methylated human serum albumin antigen was obtained by the method of Cr 0 w 1 e et al.

(J. Allergy 42: 140-156, 1968). The mice were sensitized with 0.1 injection of 0.25% methylated human serum albumin solution subcutaneously on the back of 7 to 9 mice per group. One hour after the final administration of the test compound solution, 0.1% methylated human serum albumin solution was injected subcutaneously into the left hind leg of the mouse at a dose of 0.025, and 24 hours later, the measurement method of Baba et al. (Acta Path. Jap. Vol. 27, No. 165-: 183, 1977), the thickness of the feet was measured under a stereoscopic microscope at a magnification of 10 times. The difference between the measured values before and after the antigen-induced injection was determined, and the results were shown as the average value and its standard error. All test compounds were dissolved or suspended in a 0.5% methylcellulose solution to give a test compound solution, which was orally administered for 3 consecutive days from the day of sensitization. The compound of Example 1 showed a thickness of 0.98 ± 0.12 after administration of 10 rag kg, and significantly enhanced methylated human serum albumin-induced delayed-type hypersensitivity.

 Pharmacological example 7. Effect on mouse P 3 8 8 leukemia cells

 1 X 10 "mouse P3888 leukemia cells were transplanted intraperitoneally into female CDF1 mice, and test compounds were administered intraperitoneally for 5 consecutive days (once daily) from the day after transplantation. 1 group 6 The survival and death of the mice were observed, and the Tc (%) value was calculated from the mean survival time (MST) according to the following equation.

 Ί / C (%) = (MST of the treatment group without MSTZ) × 100 As a result, the compound of Example 11 had a T / C = 2 12% at 250 mg / kg, At 0 mg / kg, T "C2 45% was exhibited.

Toxicity test

 When 100 kg of the compounds of Examples 2 and 11 were orally administered to rats, respectively, all the rats survived.

When the pharmaceutically acceptable salt of the compound of the formula (I) of the present invention is used as a medicament, it may be mixed with a suitable carrier, excipient, diluent, etc. to give powders, tablets, capsules, granules, It can be administered orally or parenterally in the form of injections, suppositories, ointments and the like. The dosage may vary depending on the patient's symptoms, weight, age, etc.For example, when administered orally for anticancer or immunosuppressive use, usually 10 to 50 rag per adult per day It is appropriate to administer several doses from one stroke. Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1

 3, 4 —Dihydro 1 3 — (2 —Black mouth phenyl) 1 6 —Chlorosulfonyl- 2 —Methyl 1 4 —Oxothieno [2,3-d) ”Bimidine

 To 140 mi of chlorosulfonate, at room temperature, 3,4-dihydro-3- (2-chlorophenyl) 1-2-methyl-14-oxothieno [2,3-d] birimidine 54.8 g Add in small portions. Heat to 70- 油 5 in an oil bath, stir for 1.5 hours, then cool the reaction mixture and carefully pour into 2 pounds of iced water. The crystals which evolve are filtered off with suction to give 65 g of the title compound with a melting point of 172-174.

Example 2

 3, 4-Jihi draw 3-(2-Methyl phenyl) 1-2-Methyl 4-Oxo 1 6-Sulfamoi noreceno [2,3-d] bilimidine

 3,4-Dihydro-3--1 (2-chlorophenyl) 1-6-Chlorosulfonyl-2-methyl-2-oxothieno [2,3-d) pyrimidine 23 g of tetrahydrofuran 20 Suspend in Omi and pour it into 20 Om of ammonia water all at once. After stirring at room temperature for 40 minutes, the reaction mixture is concentrated, water is added to the residue, and the crystals are filtered off with suction to obtain 15.8 g of the title compound having a melting point of 25'1C.

Example 3

3, 4 — dihydro 3 — (2 — methyl phenyl) 1 2 — methyl 6 — (4 — methyl 1-piperajur) sulfonyl 1 4 — Oxothieno [2,3—d] pyrimidine 'hydrochloride

 3,4—Dihidro 3 — (2—Chlocophenyl) 1 6—Chlorosulfonyl 2—Methyl 1 4—Oxothieno [2,3—d] pyrimidine 5.0 g in dichloromethan 80 m. Trimethylamine 4.5 mi and N-methylbiperazine 1.4 g are added and stirred at room temperature for 20 minutes. After washing the reaction mixture with water, the concentrated residue was added with isopropyl alcohol saturated with hydrochloric acid gas to form a hydrochloride, which was recrystallized from methanol to give the title compound having a melting point of 295-297'C. 3. Get 2 g.

Example 4

 3, 4 —Dihi draw 6 — [N— (4—acetylamino butyl) snorefa moi no] 1 3 1 (2 1-mouth phenyl) 1 2—Methyl—4—oxothieno [2, 3—d] Pyrimidine

 3, 4 —Dihydro 3 — (2 —Chlorophenyl) 1 6 —Chlorosulfonyl 1 2 —Methyl 1 4-oxothieno [2,3-d) Pyrimidine 8.0 g dichloromethan 1 50 m, 3.3 g of 4-acetylaminobutylamine and triethylamine 5.9 ^ are added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture was washed with water, and the concentrated residue was purified by silica gel chromatography to obtain 5.71 g of an oily substance, which was crystallized from ethyl acetate-hexane to give a compound having a melting point of 203 to 206 (decomposition). This gives 4.44 g of the title compound.

Example 5

 3, 4-dihydro 1 2-bucca 1 3-(2-chlorophenyl) 1 4 1 oxo 1 6-sunorefa moi luthieno [2, 3-d] pyrimidine

3, 4 — dihydro 1 3 — (2 — black phenyl) 1 2 — methyl Lou 4 Oxo 16-Sulfamoyruthieno [2,3-d) pyrimidine 10 5 5 g of acetic acid 1 加 え was added, and heated in an oil bath 100 for 1 hour 15 minutes And bromine is added dropwise. The reaction mixture is stirred under reflux for 2 hours, concentrated, and the residue is crystallized from ethanol to obtain 110 g of the title compound having a melting point of 190 to 192'C.

Example 6

 3, 4 —Dihydro 1 2 —Acetoxymethyl 1 3 — (2—Methyl phenyl) 1-4 —Oxo 1 6—Sulfamoylthieno [2,3—d] Pyrimidine

 3,4—Dihydro-1—Bromomethyl-3— (2—Chlorophenyl) 1-4—oxo1—6—Sulfamoinoreceno [2,3—d) pyrimidine 10.5 g Add 100 m of dimethylformamide and 6.0 g of sodium acetate, and stir for 2 hours at 80. The reaction mixture is poured into water, extracted with ethyl acetate, washed with water and concentrated to obtain a residue of 8.7 g. This is purified by silica gel column chromatography to obtain 5.3 g of an oily substance. This is crystallized from ethanol to obtain 3.4 g of the title compound having a melting point of 192.5 to: L94'C.

Example 7

 3, 4-dihydro (2-α-phenyl) 1 2-hydroxy 4-oxo-1 6-sulfamoyl thieno [2,3-d] birimidine

3, 4 — Jihi draw 2 — Acetoxymethyl 1 3 — (2 — Black mouth phenyl) 1 4 1 Oxo 1 6 — Srefamo i Noreceno [2, 3 — d] Pyrimidine To 9.3 g were added 200 m of methanol, 30 m of water and 14.3 m of concentrated hydrochloric acid, and the mixture was stirred and refluxed for 2 hours. Reaction mixture The residue was crystallized from methanol to give 6.2 g of pale yellow crystals, which were recrystallized from methanol to give 2.6 g of the title compound having a melting point of 255 (decomposition).

 Example 8

 3, 4 -Dihydro 1 3 — (2-chloropropenyl) 1 2 — (N-Propyl-Rubamoi Luximetyl) 1 4 — Oxo 6 — Sulfa Moi Lucieno [2, 3 — d] Biliimidin

 3, 4—Dihidro 3— (2—Cross phenyl) 1 2—Hydroxymethyl 1 4—Oxo 1 6—Sulfamoiruthieno [2,3-d) Pyrimidine 1.5 g to pyridine Add 50 mi and 2 m of puirushi cysinate, and stir at Ί5'C for 1 hour. The reaction mixture is concentrated, water is added to the residue, acidified by adding dilute hydrochloric acid, extracted with ethyl acetate, and washed with water. The concentrated residue was purified by silica gel chromatography to obtain 1.9 g of an oily substance, which was crystallized from ethanol to give the title compound having a melting point of 169 to 170'C (decomposition). 1.1 get g.

Example 9

 3, 4-dihydro (2-phenyl) 1 2-(4-methyl 1-1-piper-durmethyl) 1 4-oxo-1 6-sulfamoiluthieno [2,3-d] pyri Mijin

3, 4 — Dihydro 2-bromomethyl 1 3-(2-Krolov ヱ 2) 1 4-Oxo 1 6-Suzorefamoimoinorethieno [2,3-d] pyrimidine 5. 50 g of dimethylhonolemuamide, 1.5 g of N-methylbiperazine and 3.2 g of potassium carbonate were added to 0 g, and the mixture was added to 40 g. Stir with C for 1.5 hours. Pour the reaction mixture into water and extract with ethyl acetate Then, the concentrated residue is crystallized from ethanol and then recrystallized from methanol-π-form to obtain 1.9 g of the title compound having a melting point of 23.5 to 23.4'C (decomposed). The hydrochloride has a melting point of 2446-247'C (decomposition).

Example 10

 3,4—Dihydro 6— [N- (4-Acetylaminobutyl) sulfamoyl) -1 3— (2—Chlorophenyl) 1-2— (4—Dityl-1-biperazinylmethyl) 1 4 —Oxothieno [2,3-d) pyrimidine 'hydrochloride

 3, 4 —Dihi draw 6 — [N-(4 —acetylaminobutyl) sulfamoyl] 1 3 — (2 —black mouth fenizole) 1 2 —Methyl — 4 —oxothieno [2, 3 -d] pyri Acetic acid (50 m) is added to the midine (3 g), and bromine dissolved in 2 m of acetic acid (1.23 g) is added dropwise at 100 to 110 ° C with heating and stirring over 40 minutes. Then, after stirring at 105 for 4 hours, the reaction mixture is concentrated to obtain 4.24 g of a residue. 30 ml of dimethylformamide, 1.1 g of N-ethylbiperazine and 1 g of lithium carbonate are added to this, and the mixture is stirred at room temperature for 6 hours. The reaction mixture is poured into water, extracted with chloroform, and the concentrated residue is purified by silica gel chromatography to obtain 3.1 g of an oily substance. The hydrochloride is prepared with ethanol saturated with hydrochloric acid gas and crystallized and recrystallized from acetonitrile-ethanol to give 0.40 g of the title compound with a melting point of 160-165 ° C.

Example 1 1

3, 4 —Jihdro 1 — 3 — (2 — Black mouth) 1 2 — (4 Echiru 1 1 Pira Jurmetyl) 1 4 1 Oxo 1 6 — Sul Famoi Lucieno [2, 3 — d] Pyrimidine

 3, 4 —Dihydro 1 2 —Bromomethyl 1 3 — (2—Chlorophenyl) 1 4 —Oxo 1 6 —Sulfamoi zolethieno [2,3—d] pyrimidine 3 g to dimethylformamide 4 Add 0.8 g of 0,1-ethylbiperazine and 2.7 g of carbon dioxide rim and stir at room temperature for 1 hour. The reaction mixture was poured into water, extracted with chloroform, and the concentrated residue was purified by silica gel column chromatography, crystallized from ethyl acetate, and recrystallized from ethanol to obtain a melting point of 203 to 204. To give 320 mg of the title compound (decomposition). Example 1 2

 3, 4 dihydro 3 — (2 — phenyl) 1 2 — (4 — ethyl 1 — pyradurmethyl) 1, 5, 6 — dimethyl 1 4 oxothieno [2,3 — d] pyrimidine

 3, 4 —Jihi draw 2 —Chlorometyl 3 — (2—Chlorophenyl) 1 4 1 5, 6 —Dimecylooxothieno [2,3-d] pyrimidine 15.0 g Dissolve in black mouth form 300, add 5.8 g of potassium carbonate, drop 5.8 g of 1-ethylpyperazine, and heat to reflux for 4 hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The obtained oil is subjected to silica gel chromatography to give the title compound as a pale yellow crystal having a melting point of 126 ° C to 129 ° C 7.0. get g. This compound is converted into a hydrochloric acid salt with a hydrochloric acid-methanol solution and recrystallized to obtain 4 g of the dihydrochloride of the title compound having a melting point of 263-265 (decomposition).

Example 13

3, 4, 5, 6, 7, 8 ^ (Feninole) 1 2 — (4-Echinole-1 — Pirage, Lemetinole) 1 4 —oxo (1) Benzothieno [2,3-d} pyrimidine

 3, 4, 5, 6, 7, 8 —Hexahydro-1 2 —Chloromethyl -3-(2 —Chlorophenyl) · 1-4 —Oxo (1) benzobenzo 3-d} Pyrimidine 8.20 ra was dissolved in black mouth form 40, potassium carbonate 300 mg was added, and 1-ethylpyrazine 31 Om was added dropwise. Heat to reflux for hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to obtain an oily substance, which is purified by silica gel column chromatography. The obtained white crystals are recrystallized from ethanol to obtain 680 mg of the title compound having a melting point of 140 to 142'C.

Example 14

 3, 4 —Dihydro 1 3 — (2 —Cross phenyl) 1 6 —Ethoxycarbonyl 1 2 — (4 —Echinolei 1 —Pirajurmethyl) — 5 —Methyl 1 4 —Oxothieno [2, 3-d) Bilimidine '1/4 hydrate

16,7 g of ethyl acetate acetate, 25 g of N— (2-chlorophenyl) cyanoacetamide, 4 g of sulfur, and stirring in ethanol at room temperature in 100 Add lower morpholine 20 and stir at 50'C for 6 hours. After the sulfur remaining in the reaction solution was filtered, the reaction solution was left at room temperature overnight. The precipitated crystals were collected by filtration to give N- (2-chlorophenyl) -12-amino-5-ethoxycarbonyl-14-methylthiophene-13-carboxamide 9.4 Obtain 9 g. This is dissolved in acetic acid 10 and chloroacetyl chloride 6.3 is added, followed by refluxing for 1 hour. The reaction solution is poured into ice water, and the crystals that precipitate are collected by filtration. 8 0. After drying with C for 30 minutes, N— (2—chloro phenyl) —2—chloroacetylamino 1—4—ethoxycanoleboninole 14—methylthiophene 13—carboxamide 10 get g.

 This chloroacetylamino compound is dissolved in 120 ml of phosphorus oxychloride and refluxed for 10 hours. Crystals that form in ice water are collected by filtration, dissolved in chloroform and dried over sodium sulfate, and the chloroform is distilled off. The residue is crystallized from hexane monoethyl acetate to give 3,4-dihydrochloride. —Chloromethyltinol 3 — (2—Chlorophenyl) 1—6—Ethoxycarbone 5—Methyl-1-4—oxothieno [2,3—d] pyrimidine 2.9 g.

 The crystals are dissolved in a black form 15 and 2 g of sodium hydrogen carbonate and 1-ethylbiperazine 1.5 are added, followed by stirring at 60 ° C for 3 hours. The reaction mixture is washed with water and dried over sodium sulfate, and the form at the mouth is distilled off. The residue was purified by silica gel chromatography, crystallized with hexane-ethyl acetate, and recrystallized with the same solvent to give 0.4 g of the title compound having a melting point of 135-138'C (decomposition). Get.

Example 15

 3, 4 —Dihydro 3 — (2 —Chlorophenyl) 1 6 —Ethyl 1 2 — (4 —Ethyl 1 -Piperadurmethyl) 1 4 —Oxosotheno [2, 3 —d Pyrimidine dihydrochloride

3, 4 —Jihide mouth 2 —Chlorometinol 3 — (2—Chro phenyl) 1 6 —Ethyl 1 4-oxothieno [2,3-d) pyrimidine 1.0 g Dissolve in form 30 and add 0.50 g of potassium carbonate and 0.55 of 1-ethylbiperazine, then add 50. Stir at C for 2 hours. Wash the reaction solution with water, dry with mirabilite, and dry with nitric acid. /

 40 m are distilled off. The residue was purified by silica gel chromatography, and the resulting oil was crystallized by adding hydrochloric acid-methanol and recrystallized from methanol-ethanol to give a melting point of 240-244. 0.58 g of the title compound of (decomposition) are obtained.

 Example 16

 3,4—Dihidro 6—Bromo-3 -— (2-Chlorophenyl) —2— (4—Ethyru 1-biladulmethyl) 1-4—Oxo Thieno [2,3-d) Birimidine

 3, 4—Jihi draw 3 — (2—Methyl phenyl) 1 2—Methyl 4—Oxothieno [2,3—d] Pyrimidine 2 2.85 g is dissolved in black mouth form and N Add 19.5 g of bromosuccinimide and a trace amount of benzoyl peroxide and reflux for 10 hours. After removing the crystals precipitated in the reaction solution, the solvent was distilled off, and the residue was crystallized from hexane monoethyl acetate. As a result, 3,4-dihydro 6 with a melting point of 164.5 to 166.5'C was obtained. (2-Cross-phenyl) 1-2-methyl-4-oxothieno [2,3-d] pyrimidine 22.95 is obtained.

3, 4-Dihydro 6-Bromo-3- (2-chlorophenyl) 1-2-Methyl-4-oxothieno [2,3-d) Add acetic acid 100 ^ to bilimidine 15 and stir under reflux Then, 6.75 g of iodine was slowly dropped. The acetic acid is distilled off, and the residue is crystallized from ethanol to obtain 13.87 g of crystals. This is dissolved in dimethylformamide 10 and 3 g of potassium carbonate and 1-ethylbiperazine S are added thereto, followed by stirring at room temperature for 15 minutes. After diluting the reaction solution with Ku-form, wash with water and dry with sodium sulfate. Distill off the black form The crude product was purified by silica gel chromatography to obtain 3.4 g of an oily substance, which was crystallized from hexane monoethyl acetate and recrystallized with the same solvent to have a melting point of 155-17.5. This gives the title compound of C 750 nig. Example 17

 3, 4 —Jihi draw 3 — (2 —Krolow 4 12 trofeninole)-2-(4 -ethylpiperazinyl-1 -methyl) 1-6 -Nitro 1-4 -oxotino 2, 3 — d] bilimidine · dihydrochloride · hydrate

 3,4—Dihydro-1-3— (2—methyl phenyl) 1-2—methyl 4-oxoxothieno [2,3—d in a mixture of fuming nitric acid 100 and sulfuric acid 100 ^ under ice-cooling Add 9.56 g of bilimidine and cool on ice

30 minutes, then gradually return to room temperature and stir at room temperature for 1 hour. The reaction solution is poured into iced water, and the crystals that have formed are collected by filtration, dissolved in a black form, washed with water and aqueous sodium hydrogen carbonate, dried over sodium sulfate, and the solvent is distilled off. The residue was crystallized from ethyl monoethyl acetate to give a melting point of 166-16-18,3,4—dihydro-3- (2- (chloro-1,4-, 12-trophenyl) -12—methylinole 6 —Nitro 4-oxosothieno [2,3—d] birimidine 10.8 g is obtained.

 3, 4—Jihi draw 3— (2—Krolow 4 12 trofeninole) — 2—Metyl 6—2 tro 4—oxothieno [2> 3—d] Birimidine 5 g of acetic acid 50 In addition, 2.8 g of iodine is added dropwise under reflux with stirring, and the mixture is refluxed with stirring for 1 hour. The reaction mixture was concentrated, and the residue was crystallized from ethanol to give a melting point of 198 to 204,3,

4—Jihi Draw 2—Promo Chiru 3— (2—Chloro 4 12 Trofe Ninoré) 1 2—Me Chiru & —2 Tro 4—Oxo Thieno Γ 2> 3-d) Pyrimidine 5.65 g are obtained.

 3, 4 — Dihydro 2 — Bromomethyl 1 3 — (2 — Black 1 4 — Nitrofenisole) 1 2 — Metyl 6 — Nitro 4 — Oxo thieno [2, 3- d} Dissolve 5.6 g of pyrimidine in form of black mouth, add 2.3 g of sodium bicarbonate and 2.1-ethylbiperazine 2.1, and stir and reflux for 5 hours. The reaction solution is washed with water, dried over sodium sulfate and concentrated. The residue is purified by silica gel column chromatography, and the resulting oil is mixed with hydrochloric acid-methanol to form hydrochloride crystals, and recrystallized from methanol to obtain 0.13 g of the title compound having a melting point of at least 320'C. .

Example 18

 3, 4 — dihydro 1 3 — (2—black mouth) 1 2 — etino 1 4 — oxo 1 6 — sulfamoiruthieno [2, 3 — d] pyrimidine chlorosulfonic acid 10 ¾ £ room temperature 3, 4-Dihydro-3- (2-chlorophenyl) 1-2-ethyl 4-oxothieno [2,3-d) pyrimidine 3. Add 14 g in small portions. Heat to 70-75'C in an oil bath, stir for 1.5 hours, cool the reaction mixture, and pour into ice water. The precipitated crystals are filtered by suction, suspended in 20 ml of tetrahydrofuran, and poured into 30 ml of aqueous ammonia. After stirring at room temperature for 30 minutes, the reaction mixture is concentrated. The residue is purified by silica gel column chromatography, then crystallized from hexane monoethyl acetate and recrystallized from ethyl acetate-methanol to give the title compound 237 rag having a melting point of 25 3 X.

The compounds of Examples 19 to 58 in Table 2 are produced in the same manner as in the above Examples. 6f / x: cl8d> ョ 8068 OM /

(0 z ^

Table 2 (2)

The following compounds can be produced in the same manner as in the above Examples.

 〇3,4—Dihidro 3— (2—Fluorophenyl) -1-2—Cyclohexylcarboxyloxime Cyl-4—Oxo-1 6—Sulfa moi Lucieno [2,3—d] pyrimidine

 〇3,4—Dihydro-2-benzoyloxymethyl-1-3- (2-fluorophenyl) -14-oxo-16-Sulfamoyl luceno [2,3—d] pyrimidine

 〇3,4—Dihidro3— (2—Fluorophenyl) -1-2 — [(-(2—Froyl) 1-1-piperajuryl) methyl] -14-oxo-1-6—Sulfamoi-luthieno [2,3 — D) Pyrimidine

 〇 3, 4 —Jihi draw 3— (2-Cyanophenyl) 1 2 — [(4-Metyl 1—Pirajur) Methyl] 1 4—Oxo 1 6—Sulfa moi Lucieno [2> 3—d Pyrimidine

〇3,4-Dihidro 2 — [(4—methyl 1-piperjyl) methyl] 1 3 — (2—2 trophenyl) 1 4-oxo-1 6-sulfamoi noreceno [2, 3—d Pyrimidine

〇3,4-Dihidro 3 — (2—Fluorophenyl) 1 6 — (1 imidazolyl) Sulfonyl 2 — [((4 1 methyl 1 1 1 1 pirajur) methyl) 1 4 -oxothieno [ 2, 3 — d] pyrimidine

〇3,4 Zhihi Draw 2 — [(4— (4—ethoxybenzoyl) 1-1-piperazinyl) methyl] 1-41oxo-1 3—Fuenrou 6—Sulfamoi Norreceno [2,3—d] pirimi gin 〇3,4—Dihydro-3- (2-aminophenyl) —— 2 -— ((4-methyl-1-1-piperazinyl) methyl) -16—Sulfamoylthieno [2,3—d] pyri Mijin

 O 3, 4 —Dihydro-1-3 — (2,4-Dimethoxyphenyl) 1-2-[(4-methyl-1-biperazinyl ') methyl] 1-4 —oxo 6 —Sulfamoiruthieno [2,3— d] pyrimidine 〇 3,4 —dihidroh 2 — [(4 — ethyl-1 1 — biladul) methyl] 1 4 — oxo — 6 — sulfamoyl — 3 — (2 — trifluorome tylphenyl) Thieno [2,3—d] pyrimidine

 〇3,4—dihidroxy 2 — [((4-ethyl-1-biphenyl) methyl) 1-4—oxo-6—piperidinosulfonyl-1 3— (2—trifluorometylphenyl) thieno [2, 3-d] pyrimidine

 〇 3, 4 — dihydro 1 2 — [(4-ethyl 1 — pyridyl) methyl] 1 6 — morpholino suslephonyl 4 — oxy 1 3 — (2 — trifluorome tyl phenyl) thieno [2, 3, -d) pyrimidine

 〇 3, 4 — dihydro 1 2 — methyl 1 4 1 oxo 1 3 — fuénilu _6 — sulfamoi lucheso [2, 3 — d] pyrimidine

〇 3, 4 — Dihidro 3 — (2 — Fluorophenyl) 1 2 — Methyl 4 — Oxo 1 6 — Sulfamoylthieno [2,3-d) pyrimidine

〇 3, 4 —Jihi draw 2 —Methyl 1 4 —Oxo 1 6 —Sulfamoyl 1—3— (2-Trifluorometyl phenyl) thieno [2, 3 — d] pyrimidine

 〇 3, 4 — Jihi draw 3 — (2 — methoxyfenyl) 1 2 — Methyl 1 4 — Oxo 1 6 — Sulfa moi Noreceno [2,3 ~ d] bilimidine

 0 3, 4 —Dihydro 1 2 —Methyl 1 3 — (2—Nitrophenyl) 1 4 1oxo 1 6—Sulfa moi Lucieno [2,3-d) Birimidin

 〇 3, 4 — dihydro 2 — methyl 4 1 oxo 1 6 — sulfamoyl 3 — (2 — methyl phenyl) thieno [2,3-d] pyrimidine

 〇 3, 4 Zhihi Draw 3 — (2> 4 — Ziclo Mouth) 1 2 — Methyl 1 4 — Oxo 1 6 — Sulfa Moi Noreceno [2, 3 1 d] Pyrimidine

 〇 3, 4 ヒ 2 3 2 (2, 5 ジ ク 口 一 一 メ — メ メ — — — 3 ヒ 3 4 4 ォ ソ 6 モ ス ル モ モ 6 6

 〇 3, 4 —Dihydro 1 3 — (2, 6 —Dichloro mouth) 1 2 —Metyl 4 1oxo 1 6 —Sulfa moi luthieno [2> 3—d] pyrimidine

〇 3, 4 — dihydro 1 3 — (2 — amino) 1 2 — methyl 4-oxo 1 6 — sulfamoi noreceno [2, 3 — d] pyrimidine

〇3,4—Dihydro-1-3— (2—Hydroxyphenyl) 1-2-Metyl-4 4-Oxo-1-6—Sulfamoiruthieno [2,3—d] pyrimidine O 3, 4 —Dihydro 1-3 — (2—Methyl mouth) 1 2 —Methyl 1 6— (N—Methyl sulfamoyl) 1 4 —Oxothieno [2,3—D] pyrimidine

 〇 3, 4 —Jihi draw 3— (2—Methyl phenyl) 1 6— (N, N—Dimethyl thiolsulfamoyl) 1 2—Methyl 4—Oxoceno [2,3-d) pyrimidine

 O 3, 4 —Dihydro 3 — (2-Methyl phenyl) 1 2 -Methyl 1 4 1oxo 1 6 —Piperidino sulfonylthieno [2,3 1 d] pyrimidine

 〇 3, 4 — dihydro 1 3 — (2 — α-phenyl) 1 2 — methyl 4 4 oxo 1 6 — (1 — pyrrolidinyl) sulfonylcheno [2, 3 — d] birim gin

 〇 3, 4 — Dihidro 3 — (2 — Methyl phenol) 1 2 — Methyru 6 — Morpholinosulfonylthieno [2, 3 — d] Pyrimidine

 〇 3, 4 — dihydro 1 3 — (2 — black phenyl) 1 2 — ethyl 1 4 — oxo 1 6 — sulfamoiruthieno [2, 3-d] birimidine

 〇3,4-Dihydro-3- (2-chloro-1-phenyl) -1-4-oxo-1-2-propyl-6-sulfamoylrutieno [2,3-d] pyrimidine

 〇 3, 4 —Dihydro 2 —Butyl 1 3 — (2—Black mouth) 1 4 —Oxo 1 6 —Sulfamoi luthieno [2,3—d] pyrimidine

〇 3, 4 ヒ 1 — 3 — (2—chlorophenyl) 1 2 — Xyl-1 4 —oxo— 6 —snoreffamoiruthieno [2,3-d) pyrimidine

 〇 3, 4 — Jihi draw 2 — Penzinole 3 — (2 — Black mouth phenyl) 1 4 — Oxo 1 6 — Sunorefa Moi Noreceno [2, 3 — d] Pyrimidine

 〇 3, 4 — dihydro 1 3 — (2 — methyl phenyl) 1 2 — ethyl 1 6 — (N-ethylsnorfair) 1 4 — oxothieno [2, 3 — d] pyrimidine

 〇 3, 4 —Jihi draw 3 — (2—Cro-phenyl) 1 2—Ethyl 1 6— (N, N—Jetylsulfur Moi Nore) 1 4—Oxo thieno [2,3—d] pyrimidine

 〇 3, 4 — Jihi draw 2 — Benzinole 1 3 — (2 — Black phenyl) 1 6 — (N-ethylsulfamoyl) 1 4 — Oxocheno [2,3-d) pyrimidine

 〇 3, 4 —Dihydro 1 2 —Benzyl 1 3 — (2 —N-phenyl) -6 — (N, N—Jetylsulfamoyl) 1 4 —Oxosotheno [2,3—d] Pyrimidine

 Although the present invention has been fully described in the foregoing specification and the examples contained therein, various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

The scope of the claims  1. General formula

{Wherein, A represents a straight or branched alkylene having 1 to 4 carbon atoms. R ¹ represents hydrogen; alkyl; aryl (which may be substituted); or a group represented by N (R ⁷ ) (R ⁸ ). Provided that R ⁷ and R ⁸ are the same or different and are hydrogen; alkyl; aralkyl (the aralkyl may be substituted); aryl (the aralkyl may be substituted); Or R ⁶ and R ⁷ may form 璟 with the adjacent nitrogen atom, and the ring may further include nitrogen, oxygen, sulfur, and> N—R ⁹ optionally intervening. Good. [Where R ⁹ is hydrogen; alkyl optionally substituted with hydroxy or alkyl-substituted amino; cycloalkyl; formyl; aralkyl (the aralkyl may be substituted); (The aryl may be substituted); arylalkenyl; a heterocyclic ring; arylcarbonyl (the arylcarbonyl may be substituted); or a heterocyclic carbonyl. R ² , R ³ and R ⁴ are the same or different and represent hydrogen; halogen; hydroxy; alkyl optionally substituted by halogen; Kokishi; represents a or a ^{N (R 1 0) (R} 1 ') by a group I Table; two collected by filtration; Shiano. However, R ¹ . And R ¹¹ are the same or different and represent hydrogen; alkyl; alkanol; or arylcarbonyl (the arylcarbonyl may be substituted). R ⁵ is hydrogen; represent or alkoxycarbonyl; Nono σ plasminogen; two collected by filtration; § amino; Shiano; alkyl. R ⁶ is hydrogen; halogen; nitro; amino; cyano; alkyl; alkoxycarbonyl; nodogenated snolehoninole; - represents a ^{_{S 0 2 N (R, 2}} ) a group represented by (R ^{1 3).} Provided that R ¹² and R ¹³ are the same or different and are hydrogen; alkyl; cycloalkyl; aralkyl (the aralkyl may be substituted); aryl (the aralkyl is substituted). even though it may); § reel alkenyl; alkyl or § Li Lumpur (the Ariru whether represent Karubonirua aminoalkyl substituted with may) be substituted; nitrogen and or R ^{1 2} and R ^{1 3} are adjacent The ring may form a ring with the atom, and the ring may further optionally include nitrogen, oxygen, and> Ν—R ", where R is hydrogen; substituted by hydroxy or alkyl-substituted amino.キ シ ア ル シ シ シ シ シ シ シ シ シ シ キ ル ル ル ル ル ル ル ル ル キ ル キ キ キ キ ル キ ルAryl alkenyl; heterocyclic ring; arylcarbonyl (the arylcarbonyl may be substituted); or heterocyclic carbonyl. R ⁵ and R ⁶ are linked together to form an alkylene chain having 3 to 6 carbon atoms. It may be formed. However, when R ⁶ represents hydrogen; halogen; nitro; amino; cyano; alkyl; or alkoxycarbonyl, or R ⁵ and R ⁶ are bonded together to form a group having 3 to 6 carbon atoms. When R ¹ represents a group that forms alkylene, R ¹ represents N (R ⁷ ) (R ⁸ ) (provided that R ⁷ and R ⁸ have the same meanings as described above). When R ^s and R ⁶ are combined to form an alkylene chain having 3 to 6 carbon atoms, R ^z , R ³ and R ⁴ represent groups other than alkyl. } 3,4-dihydrothieno [2,3-d) pyrimidine compound represented by the formula: or a salt thereof. 2. Claim 1 wherein R ⁶ represents S 0 ₂ N (R ¹² ) (R ¹³ ) (where R ¹² and R ¹³ are as defined in claim 1). A compound as described. 3. R ⁶ represents hydrogen; nodogen; nitro; amino; cyano; azole; or alkoxycarbonyl, or R ⁵ and R are bonded together to form an alkylene group having 3 to 6 carbon atoms. The compound according to claim 1, wherein the compound represents a group, and ¹ represents one NCR ⁷ ) (R ⁸ ) (where R ⁷ and R ⁸ are as defined in claim 1). .  4. The compound according to claim 1, which is selected from the following compounds and salts and hydrates thereof.  3, 4 — Dihydro 1 3 — (2 — Black mouth phenyl) 1 2 — (4 -ethyl 1 — Pipera zinyl) methino 1 4 — Oxo 1 6 — Sulfamooirutieno [2, 3 — d] pyrimidine; 3, 4 —Dihydro 1 3 — (.2 —Black mouth phenyl) 1 2 — (4- Methyl-1,5-piperjur) methyl-5,6—dimethyl-4—oxothieno [2,3—d] pyrimidine;  3, 4, 5, 6, 7, 8 —hexahi draw 3 — (2 —chloro nil) 1 2 — (4 —ethyl 1 —pidra jul) methyl 1 4 —oxo (1) benzothieno [ 2,3—d] pyrimidine; 3,4—dihydro-3- (2-chlorophenyl) -1-6-ethoxycarbonyl 2— (4—ethyl-1-piperjur) Chill — 5 — methyl 4-oxothieno [2,3-d] pyrimidine; 3, 4 — dihydro 3 — (2 — chlocophenyl) 1 2 — methyl — 4 1 oxo 1 6 — sulfamoi Noreceno [2> 3-d] pyrimidine;  3, 4 —Jihi draw 3 — (2 —Chlorophenyl) 1 6 —Ethyl 1 2 — (4 —Ethyl 1 -biperazinyl) Methyl 1 4 1-oxothieno [2> 3 —d] pyrimidine;  3, 4 —Dihydro— 3 — (2 —Funoleolophenyl) 1 2 — (4 -Metyl 1 -ViperaJul) Methyl 1 4 1oxo 1 6 —Sur Famoy Lucieno [2,3- d) pyrimidine; 3, 4 — Jihi draw 3 — (2 — Black mouth feninole) 1 2 — Morpho linomethyl 4 4 oxo 1 6 — Snoreffamoiruthieno [2> 3 1 d] pyrimidine;  3, 4 —Jihi Draw 6 —Bromo 1 — (2—Cro mouth Feninole) —2— (4-Ethyru 1—Pydra Jur) Methyl 1 4—Oxo Thieno [2,3—d] pyri Midines; 3, 4 —Dihydro π — 6 —Cro 1 — 3 — (2 —Chlorophenyl) — 2 — (4 —Ethyl _ 1 -Pydra Jur) Methyl 1 4 —Oxo Thieno [2,3—d] pyrimidine;  3, 4 —Jihi draw 3 — (2 —Black mouth 4 —Nitrophenyl) — 2 — (4 —Ethyl 1 1 —Pirajur) Metyl 6 —2 Tro 1 4 —Oxothieno [2,3 — D] pyrimidine; And 3, 4 —Jihi draw 3 — (2 —Chlorophenyl) 1 2 — (4 1 Methyl 1 1 —Pirajur) Metyl 4 4Oxo 1 6 —Sulfamoylthieno [2,3-d ] Pyrimidine 5. General formula

{In the formula, A represents a linear or branched alkylene having 1 to 4 carbon atoms. R ¹ represents hydrogen; alkyl; aryl (the aryl may be substituted); or a group represented by 1 N (R ⁷ ) (R ⁸ ). However, R ⁷ and! ? ⁸ is the same or different and is hydrogen; alkyl; aralkyl (the aralkyl may be substituted); aryl (the aryl may be substituted); cycloalkyl; ⁶ and! ? ^{And 7} may form a ring together with the adjacent nitrogen atom, and the ring may further optionally include nitrogen, oxygen, sulfur, and> N—R ⁹ . [However, R ⁹ is hydrogen; alkyl optionally substituted by hydroxy or alkyl-substituted amino; cycloalkyl; formyl; Aralkyl (the aralkyl may be substituted); aryl (the aryl may be substituted); arylalkenyl; heterocycle; arylcarbonyl (the arylcarbo) Is optionally substituted); or represents a heterocyclic carbonyl. R ² , R ³ and R ⁴ are the same or different and represent hydrogen; halogen; hydroxy; alkyl optionally substituted by halogen; alkoxy; nitro; cyano; or one N (R ¹ ) (R ¹¹ ) represents a group represented by. However, R ^{1 Q} and R ¹¹ hydrogen is the same or different; Wath table or § re Rukarubo sulfonyl (the § Li Lumpur carbonyl may be substituted); alkyl; alkanol I le. R ⁵ represents hydrogen; hydrogen, rhogen, nitro, amino, cyano, alkyl; or alkoxycarbonyl. R ⁶ is hydrogen; nodogen; nitro; amino; cyano; anorekyl; alkoxy carbonyl; sulphonyl halogenate; — Represents a group represented by S 0 ₂ N (R ¹² ) (R ¹³ ). Provided that R ¹² and R ¹³ are the same or different and are hydrogen; alkyl; cycloalkyl; aralkyl (the aralkyl may be substituted); aryl (the aralkyl is substituted) Aryl alkenyl; carbonylamino alkyl substituted with alkyl or aryl (the aryl may be substituted); or R ¹² and R ¹³ are the same. The ring may form a ring with an adjacent nitrogen atom, and the ring may optionally further include nitrogen, oxygen, and> N—R ¹⁴ . Provided that R ¹⁴ is hydrogen; an alkyl which may be substituted by a hydroxy or alkyl-substituted amino; Aralkyl (the aralkyl may be substituted), aralkyl (the aralkyl may be substituted), aryl alkenyl, heterocycle, aryl carbon (the aryl) Or arylcarbonyl may be substituted); or represents a heterocyclic carbonyl. R ⁵ and R ⁶ may combine together to form an alkylene group having 3 to 6 carbon atoms. } An immunomodulator or an anticancer agent comprising a compound represented by the formula (I) or a salt thereof as an active ingredient.